The objective of this project is to determine the mechanism(s) by which sensitization and desensitization of uterine target cells to estrogen and progesterone is regulated. Though circulating levels of estrogen and progesterone vary widely during the female reproductive cycle, both hormones are present at all times to a greater or lesser extent. The intermittent dominance of estrogen and progesterone during the cycle is reversed dramatically during pregnancy as progesterone becomes the major hormonal influence despite the maintenance of significant levels of estrogens. Estrogen and progesterone action are believed to be mediated by specific receptors present in uterine target cells which cause a modulation of gene expression. The interaction of these receptor systems and their mutual agonistic and antagonistic properties within the physiological range of estrogen and progesterone levels will be the focus of this research project. Current mechanisms regulating uterine target cell response to progesterone appear to be incompatible with the chronic maintenance of progesterone action. Specifically, experiments have been designed to concurrently measure plasma steroid levels and target cell steroid receptors to test the hypotheses that: 1. progesterone can induce the replenishment of its own receptors; 2. progesterone antagonism of estrogen action is temporally limited; 3. progesterone can antagonize or modulate the action of 'weaker' estrogens e.g., estrone and estriol. In addition, a specific biochemical endpoint of progesterone action, downregulation of occupied nuclear estrogen receptor, will be used as a marker to study these mechanisms. To broaden the applicability of these observations, experiments will be conducted in both the adult female rat and hamster. Regulatory mechanisms controlling target cell sensitivity during chronic hormonal exposure will be evaluated as a model system to further our understanding of steroid hormone action during pregnancy.